Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

TitleTargeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.
Publication TypeJournal Article
Year of Publication2018
AuthorsSingh, S, Wang, Z, Shahin, MH, Langaee, TY, Gong, Y, Turner, ST, Chapman, AB, Gums, JG, McDonough, CW, Bailey, KR, Beitelshees, AL, Cooper-Dehoff, RM, Scherer, S, Boerwinkle, E, Johnson, JA
JournalPharmacogenet Genomics
Volume28
Issue11
Pagination251-255
Date Published2018 Nov
ISSN1744-6880
Abstract

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.

DOI10.1097/FPC.0000000000000353
Alternate JournalPharmacogenet. Genomics
PubMed ID30289819
PubMed Central IDPMC6262886
Grant ListU19 GM061388 / GM / NIGMS NIH HHS / United States
UL1 TR000064 / TR / NCATS NIH HHS / United States
U54 GM114838 / GM / NIGMS NIH HHS / United States
U01 GM074492 / GM / NIGMS NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
U19 GM061390 / GM / NIGMS NIH HHS / United States
UL1 TR002377 / TR / NCATS NIH HHS / United States